氨酸代谢决定PCSK9表达和PD-1阻断的抗瘤功效 在MSS结肠直肠癌中
Qi-Long Wang1, Zijie Chen2, Xiaofei Lu2
1Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
|March 24, 2025
概括
氨酸的限制抑制了结直肠癌中的PCSK9,增强了免疫治疗. 这种代谢联系为治疗微卫星稳定的结直肠癌提供了新的策略.
科学领域:
- 在瘤学瘤学.
- 代谢途径 代谢途径
- 免疫治疗是一种免疫疗法.
背景情况:
- 营养代谢显著影响癌症的进展和免疫治疗的有效性.
- 瘤微环境中的营养代谢和免疫监测之间的复杂相互作用尚未完全理解.
研究的目的:
- 研究 metionin代谢在调节瘤微环境中的免疫监测中的作用.
- 探索向PCSK9和甲胺代谢以增强癌症免疫疗法,特别是结肠直肠癌的潜力.
主要方法:
- 研究了 metionin 限制在结直肠癌 (CRC) 模型中对 PCSK9 表达的影响.
- 阐明了涉及S-adenosylmethionine (SAM),DNA甲基转移酶1 (DNMT1) 和sirtuin 6 (SIRT6) 的分子机制.
- 在CRC小鼠模型中评估PCSK9抑制和饮食氨酸限制 (DMR) 与PD-1阻断疗法结合的疗效.
主要成果:
- 发现 metionin 的限制可以抑制 CRC 中的 proprotein 转化酶 subtilisin/kexin type 9 (PCSK9) 表达.
- 从机制上讲,甲胺对SAM的代谢通过DNMT1-介导的DNA甲基化和SIRT6抑制促进PCSK9的转录.
- 在微卫星稳定 (MSS) CRC模型中,PCSK9抑制和DMR都增强了PD-1阻塞疗法和CD8+T细胞透.
- 五甲 (5-FU),PCSK9抑制和PD-1阻断的联合治疗改善了MSSCRC的治疗结果.
结论:
- 在瘤微环境中建立了氨基酸 (甲) 代谢和胆固醇代谢 (PCSK9) 之间的机制联系.
- 证明瘤细胞感知 metionin水平以调节PCSK9的表达.
- 突出显示有前途的组合治疗策略,包括MSS CRC患者的代谢调节和免疫治疗.
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